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1.
J Transl Med ; 20(1): 407, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064558

RESUMO

BACKGROUND: Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosomes are a promising cell-free therapeutic approach for the treatment of AF. The purposes of this study were to explore the mechanisms by which exosomes derived from atrial myocytes regulate atrial remodeling and to determine whether their manipulation facilitates the therapeutic modulation of potential fibrotic abnormalities during AF. METHODS: We isolated exosomes from atrial myocytes and patient serum, and microRNA (miRNA) sequencing was used to analyze exosomal miRNAs in exosomes derived from atrial myocytes and patient serum. mRNA sequencing and bioinformatics analyses corroborated the key genes that were direct targets of miR-210-3p. RESULTS: The miRNA sequencing analysis identified that miR-210-3p expression was significantly increased in exosomes from tachypacing atrial myocytes and serum from patients with AF. In vitro, the miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, miR-210-3p knock out (KO) reduced the incidence of AF and ameliorated atrial fibrosis induced by Ang II. The mRNA sequencing analysis and dual-luciferase reporter assay showed that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is a potential target gene of miR-210-3p. The functional analysis suggested that GPD1L regulated atrial fibrosis via the PI3K/AKT signaling pathway. In addition, silencing GPD1L in atrial fibroblasts induced cell proliferation, and these effects were reversed by a PI3K inhibitor (LY294002). CONCLUSIONS: Atrial myocyte-derived exosomal miR-210-3p promoted cell proliferation and collagen synthesis by inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be a novel target to ameliorate atrial fibrosis in patients with AF.


Assuntos
Fibrilação Atrial , Exossomos , Glicerolfosfato Desidrogenase , Átrios do Coração , MicroRNAs , Miócitos Cardíacos , Fibrilação Atrial/complicações , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Colágeno/metabolismo , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/metabolismo , Receptor Cross-Talk
2.
Oncoimmunology ; 11(1): 2111906, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990519

RESUMO

Cartilage oligomeric matrix protein (COMP) is an emerging regulator of tumor progression. The aim of this study was to evaluate the expression of COMP in periampullary adenocarcinoma with respect to prognostic value for survival and relapse, levels of fibrosis and infiltrating immune cells. COMP expression was evaluated using immunohistochemistry in primary tumors and subsets of paired lymph node metastases in tissue microarrays including 175 patients with periampullary adenocarcinoma. Collagen content was assessed with Sirius Red-Fast Green staining. High COMP levels were detected in cancer cells and in stroma, in 46% and 57% of the patients, respectively. High COMP expression was strongly associated with more aggressive pancreatobiliary-type (PB-type) compared to intestinal-type tumors (p < .0001). Importantly, high expression of COMP correlated with the exclusion of cytotoxic T-cells from the cancer cell compartment of the tumors, particularly in PB-type tumors. Higher levels of fibrosis measured by the density of collagen fibers correlated with high COMP levels in both cancer cells and stroma. This in turn could lead to exclusion of cytotoxic T-cells from accessing the cancer cells, a recognized immunotherapy resistance mechanism. Targeting COMP could therefore be considered as a novel therapeutic strategy in PB-type periampullary adenocarcinoma.


Assuntos
Adenocarcinoma , Ampola Hepatopancreática , Proteína de Matriz Oligomérica de Cartilagem , Neoplasias do Ducto Colédoco , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Ampola Hepatopancreática/imunologia , Ampola Hepatopancreática/patologia , Proteína de Matriz Oligomérica de Cartilagem/genética , Proteína de Matriz Oligomérica de Cartilagem/imunologia , Neoplasias do Ducto Colédoco/genética , Neoplasias do Ducto Colédoco/imunologia , Neoplasias do Ducto Colédoco/patologia , Neoplasias Duodenais , Fibrose/genética , Fibrose/imunologia , Fibrose/patologia , Expressão Gênica , Humanos , Neoplasias Pancreáticas
3.
J Clin Invest ; 132(13)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35775488

RESUMO

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-ß1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources. These important findings extend our understanding of the origin, biology, and function of fibroblasts and offer possibilities for therapeutic targeting of fibrosis in AF.


Assuntos
Fibrilação Atrial , Miocárdio , Fator de Crescimento Transformador beta1 , Fibrilação Atrial/patologia , Transição Epitelial-Mesenquimal , Fibroblastos/patologia , Fibrose/patologia , Átrios do Coração/patologia , Humanos , Miocárdio/patologia , Fator de Crescimento Transformador beta1/metabolismo
4.
Ageing Res Rev ; 79: 101662, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35688331

RESUMO

Aging promotes chronic inflammation, which contributes to fibrosis and decreases organ function. Fibrosis, the excessive synthesis and deposition of extracellular matrix components, is the main cause of most chronic diseases including aging-related organ failure. Organ fibrosis in the heart, liver, and kidneys is the final manifestation of many chronic diseases. The aryl hydrocarbon receptor (AHR) is a cytoplasmic receptor and highly conserved transcription factor that is activated by a variety of small-molecule ligands to affect a wide array of tissue homeostasis functions. In recent years, mounting evidence has revealed that AHR plays an important role in multi-organ fibrosis initiation, progression, and therapy. In this review, we summarise the relationship between AHR and the pathogenesis of aging-related tissue fibrosis, and further discuss how AHR modulates tissue fibrosis by regulating transforming growth factor-ß signalling, immune response, and mitochondrial function, which may offer novel targets for the prevention and treatment of this condition.


Assuntos
Envelhecimento , Receptores de Hidrocarboneto Arílico , Envelhecimento/patologia , Fibrose/patologia , Humanos , Rim/patologia , Fígado/patologia
5.
Dis Markers ; 2022: 6103086, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35615399

RESUMO

Diabetic renal fibrosis is a common cause of end-stage renal disease, and the circRNA-miRNA-mRNA network may play an important role in the progression of diabetic nephropathy- (DN-) induced renal fibrosis. In this study, the role of circ_000166/miR-296/SGLT2 in the process of DN-related renal fibrosis was studied by constructing an animal model of DN renal fibrosis via lentiviral transfection, plasmid transfection, and dual-luciferase reporting techniques. Compared with that of normal controls, the expression of circ_000166 in the kidney tissues of DN renal fibrosis mice substantially increased. Silencing circ_000166 could minimize kidney damage and decrease urine protein levels, thereby inhibiting the progression of renal fibrosis. Moreover, circ_000166 could act as the ceRNA of miR-296 and competitively bind to miR-296, leading to an increase in the expression of the SGLT2 gene regulated by miR-296. Through mutual verification via in vivo and in vitro experiments, miR-296 was overexpressed and SGLT2 was silenced. Results showed that DN renal fibrosis and cell apoptosis were considerably reduced. We postulate that circ_000166/miR-296/SGLT2 may become a new target in the progression of DN renal fibrosis, and the regulation of this pathway may be a promising strategy for clinical treatment of DN renal fibrosis.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , MicroRNAs , RNA Circular , Transportador 2 de Glucose-Sódio , Animais , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/genética , Células Epiteliais/metabolismo , Fibrose/etiologia , Fibrose/patologia , Redes Reguladoras de Genes , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Transdução de Sinais , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo
6.
J Mol Med (Berl) ; 100(6): 861-874, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35589840

RESUMO

Galectins are a family of proteins with at least one carbohydrate-recognition domain. Galectins are present in various tissues and organs and participate in different physiological and pathological molecular reactions in vivo. Wound healing is the basic process of traumatic disease recovery. Wound healing involves three overlapping stages: inflammation, proliferation, and remodelling. Furthermore, a comparison of wound healing with the tumour microenvironment revealed that galectin plays a key role in the wound healing process. The current review describes the role of galectin in inflammation, angiogenesis, re-epithelialisation, and fibrous scar formation and evaluates its potential as a therapeutic drug for wounds.


Assuntos
Fibrose , Galectinas , Cicatrização , Fibrose/tratamento farmacológico , Fibrose/patologia , Galectinas/metabolismo , Galectinas/farmacologia , Humanos , Inflamação , Microambiente Tumoral , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia
7.
Drug Deliv ; 29(1): 489-498, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35147052

RESUMO

For the prolonged, controlled delivery of systemic drugs, we propose an implantable drug-delivery chip (DDC) embedded with pairs of a microchannel and drug-reservoir serving as a drug diffusion barrier and depot, respectively. We pursued a DDC for dual drugs: a main-purpose drug, diclofenac (DF), for systemic exposure, and an antifibrotic drug, tranilast (TR), for local delivery. Thus, the problematic fibrotic tissue formation around the implanted device could be diminished, thereby less hindrance in systemic exposure of DF released from the DDC. First, we separately prepared DDCs for DF or TR delivery, and sought to find a proper microchannel length for a rapid onset and sustained pattern of drug release, as well as the required drug dose. Then, two distinct DDCs for DF and TR delivery, respectively, were assembled to produce a Dual_DDC for the concurrent delivery of DF and TR. When the Dual_DDC was implanted in living rats, the DF concentration in blood plasma did not drop significantly in the later periods after implantation relative to that in the early periods before fibrotic tissue formation. When the Dual_DDC was implanted without TR, there was a significant decrease in the blood plasma DF concentration as the time elapsed after implantation. Biopsied tissues around the Dual_DDC exhibited a significant decrease in the fibrotic capsule thickness and collagen density relative to the Dual_DDC without TR, owing to the effect of the local, sustained release of the TR.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/farmacologia , Implantes de Medicamento/química , Fibrose/patologia , ortoaminobenzoatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Preparações de Ação Retardada , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Liberação Controlada de Fármacos , Ratos , Ratos Sprague-Dawley , ortoaminobenzoatos/administração & dosagem , ortoaminobenzoatos/farmacocinética
8.
BMC Pulm Med ; 22(1): 49, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35105320

RESUMO

BACKGROUND: Recent studies support the diagnostic role of bronchoalveolar lavage lymphocytosis (BALL) in patients with suspected hypersensitivity pneumonitis (HP). Our study aim was to determine the spectrum of BALL findings with elimination of incorporation bias in non-fibrotic and fibrotic patients and assess correlates of positive BALL cut-off and BALL association with long-term outcomes in those with fibrotic disease (f-HP). METHODS: A single-center retrospective cohort study was pursued of patients undergoing diagnostic bronchoscopy for interstitial lung disease. Strict study enrollment was based on recent ATS/JRS/ALAT diagnostic guidance meeting 'moderate' or higher diagnostic confidence. BALL findings were assessed in both fibrotic and non-fibrotic HP patients with regression and survival analysis pursued for correlates of positive BALL cut-off and long-term outcome. RESULTS: A total of 148 patients (88 fibrotic and 60 non-fibrotic) meeting moderate or higher diagnostic confidence were included. Median BALL in f-HP was 15% compared to 19% in non-fibrotic patients, with only 28% of f-HP meeting diagnostic cut-off (≥ 30%) compared to 41% of non-fibrotic. For f-HP, centrilobular nodules on computed tomography was positively correlated with a diagnostic BALL (OR 4.07; p = 0.018) while honeycombing was negatively correlated (OR 6.9 × e-8; p = 0.001). Higher BALL was also associated with lower all-cause mortality (HR 0.98; p = 0.015). CONCLUSION: With elimination of incorporation bias, most patients with well-described HP did not meet diagnostic BALL thresholds. Higher BALL was associated with better long-term survival in those with fibrosis, but its diagnostic role may be more additive than characteristic or distinguishing.


Assuntos
Alveolite Alérgica Extrínseca/epidemiologia , Alveolite Alérgica Extrínseca/patologia , Lavagem Broncoalveolar/estatística & dados numéricos , Linfocitose/epidemiologia , Linfocitose/patologia , Idoso , Idoso de 80 Anos ou mais , Alveolite Alérgica Extrínseca/diagnóstico , Estudos de Coortes , Feminino , Fibrose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida
9.
Sci Rep ; 12(1): 1739, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110630

RESUMO

Heart failure (HF) admission is a dominant contributor to morbidity and healthcare costs in dilated cardiomyopathy (DCM). Mid-wall striae (MWS) fibrosis by late gadolinium enhancement (LGE) imaging has been associated with elevated arrhythmia risk. However, its capacity to predict HF-specific outcomes is poorly defined. We investigated its role to predict HF admission and relevant secondary outcomes in a large cohort of DCM patients. 719 patients referred for LGE MRI assessment of DCM were enrolled and followed for clinical events. Standardized image analyses and interpretations were conducted inclusive of coding the presence and patterns of fibrosis observed by LGE imaging. The primary clinical outcome was hospital admission for decompensated HF. Secondary heart failure and arrhythmic composite endpoints were also studied. Median age was 57 (IQR 47-65) years and median LVEF 40% (IQR 29-47%). Any fibrosis was observed in 228 patients (32%) with MWS fibrosis pattern present in 178 (25%). At a median follow up of 1044 days, 104 (15%) patients experienced the primary outcome, and 127 (18%) the secondary outcome. MWS was associated with a 2.14-fold risk of the primary outcome, 2.15-fold risk of the secondary HF outcome, and 2.23-fold risk of the secondary arrhythmic outcome. Multivariable analysis adjusting for all relevant covariates, inclusive of LVEF, showed patients with MWS fibrosis to experience a 1.65-fold increased risk (95% CI 1.11-2.47) of HF admission and 1-year event rate of 12% versus 7% without this phenotypic marker. Similar findings were observed for the secondary outcomes. Patients with LVEF > 35% plus MWS fibrosis experienced similar event rates to those with LVEF ≤ 35%. MWS fibrosis is a powerful and independent predictor of clinical outcomes in patients with DCM, identifying patients with LVEF > 35% who experience similar event rates to those with LVEF below this conventionally employed high-risk phenotype threshold.


Assuntos
Cardiomiopatia Dilatada , Fibrose , Insuficiência Cardíaca , Idoso , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/patologia , Estudos de Coortes , Feminino , Fibrose/complicações , Fibrose/patologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Aumento da Imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia
10.
Int J Mol Sci ; 23(3)2022 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-35163163

RESUMO

Knee arthrofibrosis is a common complication of knee surgery, caused by excessive scar tissue, which results in functional disability. However, no curative treatment has been established. E8002 is an anti-adhesion material that contains L-ascorbic acid, an antioxidant. We aimed to evaluate the efficacy of E8002 for the prevention of knee arthrofibrosis in a rat model, comprising injury to the surface of the femur and quadriceps muscle 1 cm proximal to the patella. Sixteen male, 8-week-old Sprague Dawley rats were studied: in the Adhesion group, haemorrhagic injury was induced to the quadriceps and bone, and in the E8002 group, an adhesion-preventing film was implanted between the quadriceps and femur after injury. Six weeks following injury, the restriction of knee flexion owing to fibrotic scarring had not worsened in the E8002 group but had worsened in the Adhesion group. The area of fibrotic scarring was smaller in the E8002 group than in the Adhesion group (p < 0.05). In addition, the numbers of fibroblasts (p < 0.05) and myofibroblasts (p < 0.01) in the fibrotic scar were lower in the E8002 group. Thus, E8002 reduces myofibroblast proliferation and fibrotic scar formation and improves the range of motion of the joint in a model of knee injury.


Assuntos
Ácido Ascórbico/farmacologia , Cicatriz/prevenção & controle , Fibrose/tratamento farmacológico , Artropatias/tratamento farmacológico , Traumatismos do Joelho/tratamento farmacológico , Articulação do Joelho/efeitos dos fármacos , Poliésteres/farmacologia , Aderências Teciduais/prevenção & controle , Animais , Cicatriz/metabolismo , Cicatriz/patologia , Fibrose/metabolismo , Fibrose/patologia , Artropatias/metabolismo , Artropatias/patologia , Traumatismos do Joelho/metabolismo , Traumatismos do Joelho/patologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Masculino , Membranas Artificiais , Amplitude de Movimento Articular , Ratos , Ratos Sprague-Dawley , Aderências Teciduais/metabolismo , Aderências Teciduais/patologia
11.
Cell Mol Life Sci ; 79(3): 137, 2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35182235

RESUMO

Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-ß. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.


Assuntos
Fibrose/patologia , Galectina 3/metabolismo , Nefropatias/patologia , Ativação de Macrófagos , Proteína 1 Relacionada a Twist/metabolismo , Obstrução Ureteral/complicações , Animais , Fibrose/etiologia , Fibrose/metabolismo , Galectina 3/genética , Humanos , Nefropatias/etiologia , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Proteína 1 Relacionada a Twist/genética
12.
Cell Mol Life Sci ; 79(3): 144, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35188596

RESUMO

In the cornea, the epithelial basement membrane (EBM) and corneal endothelial Descemet's basement membrane (DBM) critically regulate the localization, availability and, therefore, the functions of transforming growth factor (TGF)ß1, TGFß2, and platelet-derived growth factors (PDGF) that modulate myofibroblast development. Defective regeneration of the EBM, and notably diminished perlecan incorporation, occurs via several mechanisms and results in excessive and prolonged penetration of pro-fibrotic growth factors into the stroma. These growth factors drive mature myofibroblast development from both corneal fibroblasts and bone marrow-derived fibrocytes, and then the persistence of these myofibroblasts and the disordered collagens and other matrix materials they produce to generate stromal scarring fibrosis. Corneal stromal fibrosis often resolves completely if the inciting factor is removed and the BM regenerates. Similar defects in BM regeneration are likely associated with the development of fibrosis in other organs where perlecan has a critical role in the modulation of signaling by TGFß1 and TGFß2. Other BM components, such as collagen type IV and collagen type XIII, are also critical regulators of TGF beta (and other growth factors) in the cornea and other organs. After injury, BM components are dynamically secreted and assembled through the cooperation of neighboring cells-for example, the epithelial cells and keratocytes for the corneal EBM and corneal endothelial cells and keratocytes for the corneal DBM. One of the most critical functions of these reassembled BMs in all organs is to modulate the pro-fibrotic effects of TGFßs, PDGFs and other growth factors between tissues that comprise the organ.


Assuntos
Membrana Basal/patologia , Doenças da Córnea/patologia , Fibrose/patologia , Proteoglicanas de Heparan Sulfato/deficiência , Fator de Crescimento Transformador beta/metabolismo , Animais , Membrana Basal/metabolismo , Doenças da Córnea/genética , Doenças da Córnea/metabolismo , Fibrose/genética , Fibrose/metabolismo , Humanos , Fator de Crescimento Transformador beta/genética
13.
FASEB J ; 36(2): e22144, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34990050

RESUMO

Renal fibrosis is a progressive, fatal renal disease characterized by the aberrant accumulation of myofibroblasts that produce excess extracellular matrix (ECM) in the renal interstitium and glomeruli. Yes-associated protein (YAP) has been regarded as a crucial modulator in myofibroblast transformation, but its upstream regulator remains a mystery. In the present study investigating the participation of m6A methylation during renal fibrosis through bioinformatics analysis, we identified YTHDF1, a modulator of m6A methylation, as a key contributor for renal fibrosis because it was highly expressed in human fibrotic kidneys and had a significant correction with YAP. Their co-localization in human fibrotic kidneys was additionally shown by immunofluorescence. We then found that YTHDF1 was also up-regulated in fibrotic mouse kidneys induced by unilateral ureteral obstruction (UUO), high-dose folic acid administration, or the unilateral ischemia-reperfusion injury, further supporting a causal role of YTHDF1 during renal fibrosis. Consistent with this notion, YTHDF1 knockdown alleviated the progression of renal fibrosis both in cultured cells induced by transforming growth factor-beta administration and in the UUO mouse model. Meanwhile, YAP was accordingly down-regulated when YTHDF1 was inhibited. Furthermore, the specific binding of YTHDF1 to YAP mRNA was detected using RNA Binding Protein Immunoprecipitation, and the up-regulation of fibrotic related molecules in cultured cells induced by YTHDF1 over-expression plasmid was attenuated by YAP siRNA. Taken together, our data highlight the potential utility of YTHDF1 as an indicator for renal fibrosis and suggest that YTHDF1 inhibition might be a promising therapeutic strategy to alleviate renal fibrosis via downregulating YAP.


Assuntos
Proteínas de Ciclo Celular/genética , Fibrose/genética , Nefropatias/genética , Rim/patologia , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Regulação para Cima/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/genética , Matriz Extracelular/genética , Fibroblastos/patologia , Fibrose/patologia , Humanos , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/patologia , RNA Mensageiro/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Obstrução Ureteral/genética , Obstrução Ureteral/patologia
14.
Cell Mol Life Sci ; 79(2): 93, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35075545

RESUMO

Arterial hypertension causes left ventricular hypertrophy leading to dilated cardiomyopathy. Following compensatory cardiomyocyte hypertrophy, cardiac dysfunction develops due to loss of cardiomyocytes preceded or paralleled by cardiac fibrosis. Zyxin acts as a mechanotransducer in vascular cells that may promote cardiomyocyte survival. Here, we analyzed cardiac function during experimental hypertension in zyxin knockout (KO) mice. In zyxin KO mice, made hypertensive by way of deoxycorticosterone acetate (DOCA)-salt treatment telemetry recording showed an attenuated rise in systolic blood pressure. Echocardiography indicated a systolic dysfunction, and isolated working heart measurements showed a decrease in systolic elastance. Hearts from hypertensive zyxin KO mice revealed increased apoptosis, fibrosis and an upregulation of active focal adhesion kinase as well as of integrins α5 and ß1. Both interstitial and perivascular fibrosis were even more pronounced in zyxin KO mice exposed to angiotensin II instead of DOCA-salt. Stretched microvascular endothelial cells may release collagen 1α2 and TGF-ß, which is characteristic for the transition to an intermediate mesenchymal phenotype, and thus spur the transformation of cardiac fibroblasts to myofibroblasts resulting in excessive scar tissue formation in the heart of hypertensive zyxin KO mice. While zyxin KO mice per se do not reveal a cardiac phenotype, this is unmasked upon induction of hypertension and owing to enhanced cardiomyocyte apoptosis and excessive fibrosis causes cardiac dysfunction. Zyxin may thus be important for the maintenance of cardiac function in spite of hypertension.


Assuntos
Angiotensina II/toxicidade , Cardiomegalia/prevenção & controle , Fibrose/prevenção & controle , Hipertensão/complicações , Miócitos Cardíacos/citologia , Zixina/fisiologia , Animais , Apoptose , Pressão Sanguínea , Cardiomegalia/etiologia , Cardiomegalia/patologia , Fibrose/etiologia , Fibrose/patologia , Hipertensão/induzido quimicamente , Hipertensão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo
15.
PLoS One ; 17(1): e0262479, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35015787

RESUMO

Heart failure is a leading cause of hospitalizations and mortality worldwide. Heart failure with a preserved ejection fraction (HFpEF) represents a significant clinical challenge due to the lack of available treatment modalities for patients diagnosed with HFpEF. One symptom of HFpEF is impaired diastolic function that is associated with increases in left ventricular stiffness. Increases in myocardial fibrillar collagen content is one factor contributing to increases in myocardial stiffness. Cardiac fibroblasts are the primary cell type that produce fibrillar collagen in the heart. However, relatively little is known regarding phenotypic changes in cardiac fibroblasts in HFpEF myocardium. In the current study, cardiac fibroblasts were established from left ventricular epicardial biopsies obtained from patients undergoing cardiovascular interventions and divided into three categories: Referent control, hypertension without a heart failure designation (HTN (-) HFpEF), and hypertension with heart failure (HTN (+) HFpEF). Biopsies were evaluated for cardiac myocyte cross-sectional area (CSA) and collagen volume fraction. Primary fibroblast cultures were assessed for differences in proliferation and protein expression of collagen I, Membrane Type 1-Matrix Metalloproteinase (MT1-MMP), and α smooth muscle actin (αSMA). Biopsies from HTN (-) HFpEF and HTN (+) HFpEF exhibited increases in myocyte CSA over referent control although only HTN (+) HFpEF exhibited significant increases in fibrillar collagen content. No significant changes in proliferation or αSMA was detected in HTN (-) HFpEF or HTN (+) HFpEF cultures versus referent control. Significant increases in production of collagen I was detected in HF (-) HFpEF fibroblasts, whereas significant decreases in MT1-MMP levels were measured in HTN (+) HFpEF cells. We conclude that epicardial biopsies provide a viable source for primary fibroblast cultures and that phenotypic differences are demonstrated by HTN (-) HFpEF and HTN (+) HFpEF cells versus referent control.


Assuntos
Biomarcadores/metabolismo , Fibroblastos/patologia , Fibrose/patologia , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Hipertensão/fisiopatologia , Miocárdio/patologia , Idoso , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Fibrose/metabolismo , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Prognóstico
16.
JCI Insight ; 7(4)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35015734

RESUMO

The G protein-coupled CXC chemokine receptor 4 (CXCR4) is a candidate therapeutic target for tissue fibrosis. A fully human single-domain antibody-like scaffold i-body AD-114-PA600 (AD-114) with specific high binding affinity to CXCR4 has been developed. To define its renoprotective role, AD-114 was administrated in a mouse model of renal fibrosis induced by folic acid (FA). Increased extracellular matrix (ECM) accumulation, macrophage infiltration, inflammatory response, TGF-ß1 expression, and fibroblast activation were observed in kidneys of mice with FA-induced nephropathy. These markers were normalized or partially reversed by AD-114 treatment. In vitro studies demonstrated AD-114 blocked TGF-ß1-induced upregulated expression of ECM, matrix metalloproteinase-2, and downstream p38 mitogen-activated protein kinase (p38 MAPK) and PI3K/AKT/mTOR signaling pathways in a renal proximal tubular cell line. Additionally, these renoprotective effects were validated in a second model of unilateral ureteral obstruction using a second generation of AD-114 (Fc-fused AD-114, also named AD-214). Collectively, these results suggest a renoprotective role of AD-114 as it inhibited the chemotactic function of CXCR4 as well as blocked CXCR4 downstream p38 MAPK and PI3K/AKT/mTOR signaling, which establish a therapeutic strategy for AD-114 targeting CXCR4 to limit renal fibrosis.


Assuntos
Regulação da Expressão Gênica , Nefropatias/genética , Rim/patologia , Receptores CXCR4/genética , Regulação para Cima , Animais , Linhagem Celular , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Humanos , Rim/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR4/biossíntese , Transdução de Sinais
17.
JCI Insight ; 7(4)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35025763

RESUMO

Aristolochic acid (AA) is the causative nephrotoxic alkaloid in AA nephropathy, which results in a tubulointerstitial fibrosis. AA causes direct proximal tubule damage as well as an influx of macrophages, although the role of macrophages in pathogenesis is poorly understood. Here, we demonstrate that AA directly stimulates migration, inflammation, and ROS production in macrophages ex vivo. Cells lacking interferon regulatory factor 4 (IRF4), a known regulator of macrophage migration and phenotype, had a reduced migratory response, though effects on ROS production and inflammation were preserved or increased relative to WT cells. Macrophage-specific IRF4-knockout mice were protected from both acute and chronic kidney effects of AA administration based on functional and histological analysis. Renal macrophages from kidneys of AA-treated macrophage-specific IRF4-knockout mice demonstrated increased apoptosis and ROS production compared with WT controls, indicating that AA directly polarizes macrophages to a promigratory and proinflammatory phenotype. However, knockout mice had reduced renal macrophage abundance following AA administration. While macrophages lacking IRF4 can adopt a proinflammatory phenotype upon AA exposure, their inability to migrate to the kidney and increased rates of apoptosis upon infiltration provide protection from AA in vivo. These results provide evidence of direct AA effects on macrophages in AA nephropathy and add to the growing body of evidence that supports a key role of IRF4 in modulating macrophage function in kidney injury.


Assuntos
Apoptose , DNA/genética , Fatores Reguladores de Interferon/genética , Túbulos Renais Proximais/metabolismo , Macrófagos/metabolismo , Mutação , Insuficiência Renal Crônica/genética , Animais , Ácidos Aristolóquicos/toxicidade , Células Cultivadas , Análise Mutacional de DNA , Modelos Animais de Doenças , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Deleção de Genes , Fatores Reguladores de Interferon/metabolismo , Túbulos Renais Proximais/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia
18.
J Appl Physiol (1985) ; 132(3): 653-672, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35050792

RESUMO

In Duchenne muscular dystrophy (DMD), diaphragm muscle dysfunction results in respiratory insufficiency, a leading cause of death in patients. Increased muscle stiffness occurs with buildup of fibrotic tissue, characterized by excessive accumulation of extracellular matrix (ECM) components such as collagen, and prevents the diaphragm from achieving the excursion lengths required for respiration. However, changes in mechanical properties are not explained by collagen amount alone and we must consider the complex structure and mechanics of fibrotic tissue. The goals of our study were to 1) determine if and how collagen organization changes with the progression of DMD in diaphragm muscle tissue and 2) predict how collagen organization influences the mechanical properties of the ECM. We first visualized collagen structure with scanning electron microscopy (SEM) images and then developed an analysis framework to quantify collagen organization and generate image-based finite-element models. Image analysis revealed increased collagen fiber straightness and alignment in mdx over wild type (WT) at 3 mo (straightness: mdx = 0.976 ± 0.0108, WT = 0.887 ± 0.0309, alignment: mdx = 0.876 ± 0.0333, WT = 0.759 ± 0.0416) and 6 mo (straightness: mdx = 0.942 ± 0.0182, WT = 0.881 ± 0.0163, alignment: mdx = 0.840 ± 0.0315, WT = 0.759 ± 0.0368). Collagen fibers retained a transverse orientation relative to muscle fibers (70°-90°) in all groups. Mechanical models predicted an increase in the transverse relative to longitudinal (muscle fiber direction) stiffness, with stiffness ratio (transverse/longitudinal) increased in mdx over WT at 3 mo (mdx = 5.45 ± 2.04, WT = 1.97 ± 0.670) and 6 mo (mdx = 4.05 ± 0.985, WT = 1.96 ± 0.506). This study revealed changes in diaphragm ECM structure and mechanics during disease progression in the mdx muscular dystrophy mouse phenotype, highlighting the need to consider the role of collagen organization on diaphragm muscle function.NEW & NOTEWORTHY Scanning electron microscopy images of decellularized diaphragm muscle from WT and mdx, Duchenne muscular dystrophy model, mice revealed that collagen fibers in the epimysium are oriented transverse to muscle fibers, with age- and disease-dependent changes in collagen arrangement. Finite-element models generated from these images predicted that changes in collagen arrangement during disease progression influence the mechanical properties of the extracellular matrix. Thus, changes in collagen fiber-level structure are implicated on tissue-level properties during fibrosis.


Assuntos
Colágeno , Diafragma , Fibrose , Distrofia Muscular de Duchenne , Animais , Colágeno/ultraestrutura , Diafragma/patologia , Modelos Animais de Doenças , Fibrose/complicações , Fibrose/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Microscopia Eletrônica de Varredura , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/patologia
19.
Life Sci ; 288: 120164, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34822794

RESUMO

Renal ischemia/reperfusion (I/R) injury is a major clinical problem because it can cause acute kidney injury (AKI) or lead to the transition from AKI to chronic kidney disease (CKD). Oxidative stress, which involves the production of reactive oxygen species (ROS), plays an important role in the development and exacerbation of I/R-induced kidney injury. However, we have previously reported that lecithinized superoxide dismutase (PC-SOD), a SOD derivative with high tissue affinity and high stability in plasma, has beneficial effects in various disease models because of its inhibitory effect on ROS production. Therefore, we aimed to determine the effects of intravenous PC-SOD administration in a mouse model of renal injury induced by I/R. PC-SOD markedly ameliorated the I/R-induced increases in markers of renal damage (urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and interleukin-6) and tubular necrosis 48 h after the intervention. We also found that PC-SOD significantly ameliorated the I/R-induced increase in ROS production, using an ex vivo imaging system. Furthermore, PC-SOD inhibited the increases in expression of markers of fibrosis (α-smooth muscle actin and collagen 1A1) 96 h after, and renal fibrosis 25 days after I/R was induced. Finally, we found that PC-SOD ameliorated the I/R-induced AKI in mice with high-fat diet-induced prediabetes. These results suggest that PC-SOD inhibits AKI and the transition from AKI to CKD through the inhibition of ROS production. Therefore, we believe that PC-SOD may represent an effective therapeutic agent for I/R-induced renal injury.


Assuntos
Injúria Renal Aguda/prevenção & controle , Modelos Animais de Doenças , Fibrose/prevenção & controle , Estresse Oxidativo , Fosfatidilcolinas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/complicações , Superóxido Dismutase/administração & dosagem , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Dieta Hiperlipídica , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR
20.
J Histochem Cytochem ; 70(1): 53-81, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34751050

RESUMO

Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/ß-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/ß-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field.


Assuntos
Carcinoma Hepatocelular/terapia , Fibrose/terapia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Neoplasias Hepáticas/terapia , Nicho de Células-Tronco/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Fibrose/imunologia , Fibrose/patologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Nicho de Células-Tronco/imunologia
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